Premature ejaculation (PE), also known as rapid ejaculation, is defined as occurring if the man persistently or recurrently ejaculates in response to minimal stimulation before, during, or shortly after penetration and before the patient (or partner) wishes it. Premature ejaculation is mainly caused by psychological factors. It has hereditary characteristics and abnormality in the neuron or other networks can also contribute to premature ejaculation. Premature ejaculation is one of quite common sexual dysfunctions and ⅓ of men suffer from premature ejaculation.
According to WHO, premature ejaculation is quantitatively defined as the intravaginal ejaculation latency time (IELT) is 60 seconds or less. It is known that ejaculation delay is related to the activation of 5HT2c, while rapid ejaculation is associated with 5HT1a. It is assumed that the low level of 5HT (serotonin) neurotransmission, the hypofunction of 5HT2c receptor, or the hyperfunction of 5HT1a leads to premature ejaculation. It can also be related to other factors including hypersensitivity of nervous system, penis sensitivity, somatic cell-vulnerability, deterrent effect of the serotonin operating system, etc. (US Publication No. 2007-0043030; Trends in Neuroscience, 2007, (30):79-84).
Premature ejaculation is the most common symptom of the male sexual dysfunction, but there has not been conducted insufficient research thereon. A research by Masters and Johnson in 1970 announcing that premature ejaculation could be easily fixed by behavior therapy was the established theory, and the cause of the premature ejaculation was considered as similar to that of impotence or libido degradation. However, it has been found that behavior therapy has the limits and the medical treatment of premature ejaculation came to attention in 1990s.
In the early stage of medical treatment of premature ejaculation, clomipramine (Anafranil®) which is a representative tricyclic antidepressant (TCAs) was used. There is reported the ejaculation latency effect by medicating clomipramine with the oral dose of 25 mg or 50 mg per day (J Clin Psychiatry. 1995, (56):402-407). Further, it is reported that when 50 mg of clomipramine was administered to premature ejaculation patients with an average age of 44, some side effects including constipation, dry-mouth, nausea, drowsiness, headache and dizziness, etc. were shown up, although ejaculation was delayed (The Journal of Urology, 1998, (159):425-427). Such side effects occur since clomipramine affect not only serotonin but also other neurotransmitters.
For the above problems, researchers have begun to focus on a Selective Serotonin Reuptake Inhibitor (SSRI) for the treatment of premature ejaculation. Sertraline (Zoloft®), one of representative SSRIs, was used for the treatment of premature ejaculation. It is reported that when 50 mg to 200 mg per day of sertraline was administered to premature ejaculation patients, while the ejaculation was delayed, side effects including nausea, vomiting, etc. also occurred and such side effects lead to lowering the medication effect (The Journal of Urology, 1998, (159):1935-1938; U.S. Pat. No. 4,940,731).
Among other SSRIs, fluoxetine (Prozac®), known as an antidepressant, was administered for the treatment of premature ejaculation. U.S. Pat. No. 5,151,448 describes that fluoxetine was administered to the patients with premature ejaculation. Also, as reported in The Journal of Urology, 1998, (159):425-427, 40 mg of fluoxetine was administered to premature ejaculation patients, but the ejaculation delay effect was weak. Besides, the side effects including drowsiness, dry-mouth, nausea, vomiting, etc. were reported. When fluoxetine was administered to premature ejaculation patients as shown in The Journal of Urology, 2003, (170):164-165, the side effects such as nausea, headache, and insomnia occurred. Therefore, fluoxetine cannot be successfully used for the treatment of premature ejaculation.
U.S. Pat. No. 6,495,154 describes a rapid-release pharmaceutical formulation containing clomipramine which can be conveniently administered on demand, but did not suggest concrete solutions to the side effects mentioned above. US Publication No. 2007-0043030 also describes a composition for pulmonary inhalation comprising clomipramine in order to accomplish rapid treatment effect and to reduce side effects. However, there was no concrete results showing the treatment effect of medicine and diminishing the side effects. Furthermore, there is not suggested any combinational compositions of various antidepressants or other therapeutic agents.
Therefore, new therapeutic agents for the treatment of premature ejaculation, which has effective and excellent treatment effects and reduce side effects like nausea, vomiting, drowsiness, sedation effect, awakening effect, and weight-loss, etc. has been required in the relevant industry.